Pulsed cavitational ultrasound therapy

Abstract

Therapy methods using pulsed cavitational ultrasound therapy can include the subprocesses of initiation, maintenance, therapy, and feedback of the histotripsy process, which involves the creation and maintenance of ensembles of microbubbles and the use of feedback in order to optimize the process based on observed spatial-temporal bubble cloud dynamics. The methods provide for the subdivision or erosion of tissue, liquification of tissue, and the enhanced delivery of therapeutic agents. Various feedback mechanisms allow variation of ultrasound parameters and provide control over the pulsed cavitational process, permitting the process to be tuned for a number of applications. Such applications can include specific tissue erosion, bulk tissue homogenization, and delivery of therapeutic agents across barriers.

1 . A method for controlled mechanical sub-division of soft tissue within a tissue volume, said method comprising:
 outputting an initiation sequence directed at nuclei within cells of the soft tissue resulting in cavitation within the cells;   detecting formation of a bubble cloud in the soft tissue resulting from said cavitation within the cells;   outputting a bubble cloud sustaining sequence; and   outputting a therapy sequence which interacts with said bubble cloud to produce homogenization of the cell of the soft tissue.   
   
   
       2 . A method according to  claim 1 , further comprising:
 detecting cessation of said bubble cloud.   
   
   
       3 . A method according to  claim 2 , further comprising:
 re-outputting said initiation sequence in response to said cessation of said bubble cloud.   
   
   
       4 . A method according to  claim 2 , further comprising:
 re-outputting said bubble cloud sustaining sequence prior to said cessation of said bubble cloud.   
   
   
       5 . A method according to  claim 1  wherein said outputting an initiation sequence comprises outputting an initiation sequence at a frequency equal to a frequency of at least one of said bubble cloud sustaining sequence and said therapy sequence. 
   
   
       6 . A method according to  claim 1  wherein said outputting an initiation sequence comprises outputting an initiation sequence operable to create at least one of a vapor cloud or a plasma cloud. 
   
   
       7 . A method according to  claim 1  wherein said outputting an initiation sequence comprises outputting an initiation sequence causing an ionizing radiation bubble chamber effect. 
   
   
       8 . A method according to  claim 1  wherein said outputting an initiation sequence comprises mechanically injecting cavitation nuclei. 
   
   
       9 . A method according to  claim 8  wherein said mechanically injecting cavitation nuclei comprises mechanically injecting cavitation nuclei intravascularly. 
   
   
       10 . A method according to  claim 8  wherein said mechanically injecting cavitation nuclei comprises mechanically injecting cavitation nuclei into a therapy volume. 
   
   
       11 . A method according to  claim 1 , further comprising:
 targeting a therapeutic agent at a predetermined location in the soft tissue to enhance enucleation of dissolved gases in the soft tissue.   
   
   
       12 . A method according to  claim 11  wherein said targeting a therapeutic agent comprises targeting a therapeutic agent selected from the group consisting essentially of enzymes, proteins, and proto-bubble droplets. 
   
   
       13 . A method according to  claim 1  wherein said outputting an initiation sequence comprises mechanically stimulating the soft tissue to generate cavitation nuclei. 
   
   
       14 . A method according to  claim 1  wherein said outputting an initiation sequence comprises thermally stimulating the soft tissue to generate vapor nuclei. 
   
   
       15 . A method according to  claim 1 , further comprising:
 interleaving said bubble cloud sustaining sequence and said therapy sequence.   
   
   
       16 . A method according to  claim 1  wherein said outputting a bubble cloud sustaining sequence comprises optically stimulating said bubble cloud to generally maintain said bubble cloud. 
   
   
       17 . A method according to  claim 1  wherein said outputting a bubble cloud sustaining sequence comprises stimulating said bubble cloud via ionizing radiation to generally maintain said bubble cloud. 
   
   
       18 . A method according to  claim 1  wherein said outputting a bubble cloud sustaining sequence comprises mechanically stimulating said bubble cloud to generally maintain said bubble cloud. 
   
   
       19 . A method according to  claim 1  wherein said outputting a bubble cloud sustaining sequence comprises thermally stimulating said bubble cloud to generally maintain said bubble cloud. 
   
   
       20 . A method for controlled mechanical sub-division of soft tissue within a tissue volume, said method comprising:
 actuating a transducer to output an initiation pulse sequence directed at nuclei within cells of the soft tissue resulting in cavitation within the cells;   detecting initiation of a bubble cloud in the soft tissue resulting from said cavitation within the cells in response to said initiation pulse sequence;   actuating said transducer to output a bubble cloud maintenance and sustaining pulse sequence; and   actuating said transducer to output a therapy pulse sequence which generates and interacts with said bubble cloud to homogenize the cells of the soft tissue.   
   
   
       21 . The method according to  claim 20  wherein said detecting initiation of said bubble cloud in the soft tissue in response to said initiation pulse sequence comprising detecting initiation of said bubble cloud in the soft tissue in response to said initiation pulse sequence using feedback techniques. 
   
   
       22 . The method according to  claim 21 , further comprising:
 detecting cessation of said bubble cloud.   
   
   
       23 . The method according to  claim 22  wherein said detecting cessation of said bubble cloud comprises detecting cessation of said bubble cloud using said feedback techniques. 
   
   
       24 . The method according to  claim 23  wherein said feedback techniques are chosen from the group consisting of acoustic backscatter detection, optical attenuation detection, electrical impedance tomography, low frequency hydrophone detection, ultrasound imaging, magnetic resonant imaging, and combinations thereof. 
   
   
       25 . The method according to  claim 23  wherein said an ultrasound imaging device to detect and monitor said bubble cloud comprises employing an ultrasound imaging device to detect and monitor said bubble cloud while simultaneously actuating said transducer. 
   
   
       26 . A method according to  claim 23  wherein at least one of said detecting initiation of a bubble cloud in the soft tissue and cessation of said bubble cloud comprises employing optical feedback. 
   
   
       27 . A method according to  claim 23  wherein at least one of said detecting initiation of a bubble cloud in the soft tissue and said detecting cessation of said bubble cloud comprises employing acoustic feedback. 
   
   
       28 . A method according to  claim 23  wherein at least one of said detecting initiation of a bubble cloud in the soft tissue and said detecting cessation of said bubble cloud comprises employing a transducer detecting reflection from said bubble cloud of at least one of said initiation pulse sequence and maintenance and sustaining pulse sequence and therapy pulse sequence. 
   
   
       29 . The method according to  claim 22  wherein said detecting cessation of said bubble cloud is performed simultaneously with said actuating said transducer to output said bubble cloud maintenance and sustaining pulse sequence. 
   
   
       30 . The method according to  claim 22 , further comprising:
 re-actuating said transducer to output said initiation pulse sequence in response to said detecting cessation of said bubble cloud.   
   
   
       31 . The method according to  claim 22 , further comprising:
 re-actuating said transducer to output said therapy pulse prior to said cessation of said bubble cloud.   
   
   
       32 . The method according to  claim 20  wherein said actuating a transducer to output said initiation pulse sequence comprises actuating a transducer to output high intensity ultrasound pulses which generate said bubble cloud and produce cavitation nuclei in a treatment volume, said cavitation nuclei reducing a cavitation threshold. 
   
   
       33 . The method according to  claim 20  wherein said maintenance and sustaining pulse sequence comprises a pulse intensity lower than or equal to a pulse intensity of said initiation pulse sequence. 
   
   
       34 . The method according to  claim 20  wherein said actuating said transducer to output a bubble cloud sustaining sequence comprises actuating said transducer to output a bubble cloud sustaining sequence without thermally degrading said soft tissue. 
   
   
       35 . The method according to  claim 20  wherein said detecting initiation of said bubble cloud is completed simultaneously with said actuating said transducer to output an initiation pulse sequence. 
   
   
       36 . The method according to  claim 20  wherein said initiation pulse sequence, said bubble cloud maintenance and sustaining pulse sequence, and said therapy pulse sequence comprise ultrasound pulses having at least one identical acoustic parameter chosen from the group consisting of acoustic frequency, pulse duration, pulse intensity, pulse repetition frequency and pulse pressure. 
   
   
       37 . The method according to  claim 20  wherein said initiation pulse sequence, said bubble cloud maintenance and sustaining pulse sequence, and said therapy pulse sequence comprise identical output from said transducer. 
   
   
       38 . A method for controlled mechanical sub-division of soft tissue within a tissue volume, said method comprising:
 actuating a first transducer to output an initiation pulse sequence directed at nuclei within cells of the soft tissue resulting in cavitation within the cells;   detecting initiation of a bubble cloud in the soft tissue resulting from said cavitation within the cells in response to said initiation pulse sequence;   actuating a second transducer to output a bubble cloud maintenance and sustaining pulse sequence; and   actuating a third transducer to output a therapy pulse sequence which generates and interacts with said bubble cloud to homogenize the cells of the soft tissue.   
   
   
       39 . The method according to  claim 38  wherein at least one of said first transducer, said second transducer, and said third transducer is different than the remaining transducers.